There is increasing evidence that the manifestations of atherosclerotic vascular disease are primarily due to the progression of the atherosclerotic lesion to a fibrous plaque which ultimately narrows the arterial lumen. The major goals of the proposal are (1) to determine the usefulness of antimitotic, antiinflammatory and connective tissue inhibiting drugs in the prevention of fibrous plaque formation and managemet of atherosclerosis and coronary heart disease and (2) to elucidate the role of connective tissue and arterial smooth muscle cells in the pathogenesis of these diseases. The potential use and mode of action of these agents in atherosclerosis will be evaluated in the rabbit and in the Macaca irus monkey. The morphological changes in the arteries will be correlated with the biochemical and metabolic changes in the lipids and connective tissue proteins contained in the arteries (elastin, collagen, glycoproteins and mucopolysaccharides). Arterial smooth muscle cells grown in tissue culture also will be used to study the effects of these drugs on the metabolism of connective tissue proteins. Recents studies by our group in experimental atherosclerosis in rabbits indicate that the connective tissue inhibitor, penicillamine and the antiinflammatory agent, aspirin, suppress collagen deposition in the plaque while the antimitotic agent, colchicine inhibits both collagen and foam cell proliferation. In view of the inhibitory effects of colchicine and aspirin on fibrous plaque formation in the rabbit and the potential use of these agents in human vascular disease, it is planned to evaluate their effects on the progression and regression of coronary atherosclerosis and coronary atherosclerotic heart disease in the Macaca irus monkey. The proposed studies may lead to new approaches to the control of atherosclerotic vascular disease as well as to an enhanced understanding of the role of connective tissue proteins and arterial smooth muscle cells in this disease.